Red face related skin disorders, which share symptomatic similarities and probably pathological causes, include rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis and contact dermatitis. These red face related conditions may range from feelings of heat and sensitivity to flushing or burning with intense sensitivity. Patients with red face related skin disorders often exhibit extreme sensitivity to environmental and topical factors. Steroid-induced rosacea-like dermatitis (or steroid rosacea) is papular or pustular lesions with erythematous and edematous base with or without telangiectasia, which is caused by prolonged application of topical steroids to the face or as a rebound condition after discontinuation of topical steroids.
Dermatologic toxicities are known cutaneous adverse events associated with targeted therapies or immunotherapy and share similar symptoms and probable pathologic causes of the red face-related skin disorders. Targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, multityrosine kinase (MTK) inhibitors, MEK inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, protein kinase B (AKT) inhibitors, BRAF inhibitors, HER2 inhibitor, multikinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multikinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and retinoid X receptor (RXR) agonists; immunotherapies such as cancer vaccines, cytokine agents (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), interferons, and interleukin-2 (IL-2)), cell therapies (e.g., tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR)-engineered peripheral blood lymphocytes (PBL), and chimeric antigen receptor (CAR)-engineered PBL), immune checkpoint protein inhibitors (e.g., PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA, and TIGIT), and immune checkpoint protein stimulators (e.g., CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1, and CD-40); or a combination of any of the above therapies could induce toxicities including papulopustular rash, maculopapular rash, erythema, telangiectasias flushing, paronychia and fissure, hair changes, xerosis, mucositis, pruritus, and hand-foot skin reaction, which may occur in more than 90% of patients and may also superinfected with bacteria, such as staphylococcus aureus (Wollenberg, Kroth et al., Cutaneous side effects of EGFR inhibitors—appearance and management, Dtsch Med Wochenschr 2010; Lacouture, Maitland et al., A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCO skin toxicity study group, Support Care Cancer, 2010; Curry, Torres-Cabala et al., Dermatologic toxicities to targeted cancer therapy: shared clinical and histologic adverse skin reactions, International Journal of Dermatology, 2014; Jeffrey S. Weber et. al., Toxicities of Immunotherapy for the Practitioner, Journal of Clinical Oncology, Vol. 33, 2015; Grace K. Dy and Alex A. Adjei, Understanding, Recognizing, and Managing Toxicities of Targeted Anticancer Therapies, CA Cancer J Clin, Vol. 63, 2013; Ahmad Tarhini, Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management, Scientifica, 2013; J Larkin et al., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma, N. Engl. J. Med., Vol. 373, 2015). Histopathologic findings of such skin toxicities showed that inflammation is frequently involved and leads to acneiform skin rash. A papulopustular rash was more frequently reported on EGFR inhibitors like cetuximab (83% of patients) and afatinib (90% of patients), and MEK inhibitors like selumetinib (93% of patients) and trametinib (80% of patients) therapy. A maculopapular rash was more commonly described with PI3K inhibitors like BKM-120 (37% of patients), MK2206 (52% of patients) therapy, immune checkpoint protein inhibitors like anti-CTLA-4 inhibitor ipilimumab (33% of patients), anti-PD-1 inhibitor nivolumab (26% of patients), or combination of ipilimumab and nivolimumab (more than 40% of patients).
Berberine (Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo (5,6-a) quinolizinium) is an isoquinoline alkaloid present in herb plants, such as coptis (Coptidis rhizome), phellodenron, Scutellaria baicalensis, Mahonia aquifolium and berberis. Berberine and its derivatives have been found to have antimicrobial and antimalarial activities. It can act against various kinds of pathogens such as fungi, saccharomycete, parasite, bacterium and virus.
Berberine also has anti-inflammatory function, yet the exact mechanism is unknown.
U.S. Pat. No. 6,440,465 pertains to topical skin formulations of glucosamine in an emollient base which contains berberine for the treatment of psoriasis. U.S. Patent Publication No. 2005/0158404 pertains to a nutritional product, dietary supplement or pharmaceutical composition which contains vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and an herbal source of berberine for the treatment of acne in oral administration, U.S. Pat. No. 6,974,799 relates to topical compositions comprising a tripeptide (N-palmitoyl-Gly-His-Lys) and a tetrapeptide (N-palmitoyl-Gly-Gln-Pro-Arg) for the treatment of visible signs of aging including wrinkles, stretch marks, dark circles. The formulation may contain additional ingredients, including berberine. In these inventions, berberine is included as one of the many ingredients and its concentration is not specified.
U.S. Patent Publication 2004/0146539 relates to topical nutraceutical compositions with body slimming and tone-firming anti-aging benefits that may be used to treat skin aging, skin wrinkle, skin exfoliating, acne, rosacea and other skin problems. The composition of this invention includes antimicrobial agents selected from several agents including berberine. In these nutraceutical compositions, berberine is included as one of the many ingredients and its concentration is not specified. There has been a 10% Mahonia aquifolium cream (Relieva™, Apollo Pharmaceutical Canada Inc) containing 0.1% berberine for the treatment of psoriasis.
U.S. Patent Publication 2012/0165357 discloses the use of berberine to treat various red face related skin disorders but it does not disclose any specific formulations of berberine that would be found to be effective for the treatment of specific conditions.
Therefore, there is still a need to develop new effective methods for the treatment of various red face related skin disorders as well as dermatologic toxicities induced by targeted therapy and/or immunotherapy.